In vivo profiling

Owing to a curious overlap of interest in different laboratories, this class of vanilloid antagonists is better investigated than others with regards to both structure-activity relationships and in vivo profile of activities. 

Bayer [199-203] has claimed in a series of patents a number of aryl sulfonyl esters as cannabinoid agonists for the treatment and prophylaxis of neurodegenerative diseases. Following on from this a number of publications detailing the in vitro and in vivo profiles on two of these compounds, BAY 38-7271 (317) and BAY 59-3074 (318), have been published. 

From the indole carbazimidamides investigated, tegaserod (R5 = OMe, R9 = n-pentyl), a potent partial 5-HT4 agonist, was selected for clinical development for the treatment of functional motility disorders based on its overall in vitro and in vivo profile. 

A related series of diaryl pyrrolo[l,2-a]imidazoles, represented by SK F 104351 (149), 104493 (150) and 105809 (151), has been reported to show similar profiles [360,366]. In mice and rats, SK F 105809 was a prodrug for the active methyl sulphide SK F 105561 (152), which was about 10-fold more potent in vitro than SK F 86002 [367]. The in vivo profile of SK F 105809, which is reported to be in clinical trials, was similar to that of SK F 86002. 

A summary of the in vitro and in vivo profile of zileuton (136) has appeared [492]. A review of hydroxamic acids and hydroxyureas emphasized work at Burroughs Wellcome, but included information on zileuton as well... 

Prospects for In Vivo Profiling of Hits and Leads for Genotoxicity... 

Metabolism of the anti-malarial amodiaquine provides quinone-imine, which is an electrophilic metabolite responsible for hepatotoxicity and agranulocytosis. These side effects have severely restricted the clinical use of amodiaquine. The replacement of the phenolic hydroxyl by a fluorine prevents from oxidation process. Then, the A/-dealkylation becomes the major process. This has led to further refinements, with the preparation of the A/-f-butyl analogue, a compound which resists towards metabolic side-chain cleavage and has an excellent in vitro and in vivo profile (Fig. 15) [56]. 

Another significant factor is the range of release rates studied. The release rates, as measured by percent dissolved, for each formulation studied, should differ adequately (e.g., by 10%). This should result in in vivo profiles that show a comparable difference, for example, a 10% difference in the pharmacokinetic parameters of interest (Cmax or AUC) between each formulation. 

This approach also has been employed in the design of naltrexone-derived ligands with mu agonist/delta antagonist properties [75,76]. One such compound, 30 (SoRI 9409), was reported not to induce tolerance in mice and produced fewer withdrawal signs when challenged with naloxone in acute and chronic morphine dependence models [75]. However, discrepancy between the in vivo/in vitro data requires additional investigation in order to better define the mechanism of the improved in vivo profile [76,77]. 

Roeloffs R, Wickenden AD, McNaughton-Smith G, Jones L, Harrison W, Porreca F, Rigdon GC (2005) In vivo profile of ICA-27243, a potent and selective KCNQ2/3 activator in rodent models of pain. Soc Neurosci, online, P152.14... 

C26-(l,3-dioxolanyl)-12,13-Epo D 20 (Figure 1-3) exhibits enhanced in vitro antiproliferative activity over Epo but it was found to be significantly less efficacious than Epo D in vivo. In contrast, C26-fluoro-Epo B 21 (Figure 1-3), which exhibits comparable in vitro antiproliferative activity with Epo was demonstrated to possess significantly better antitumor activity than paclitaxel in a human prostate xenograft model when both compounds were administered at equitoxic doses.No comparison with Epo B was included in this work, but data from our laboratory indicate that the in vivo profile of C26-fluoro-Epo B is similar to... 

These extended-chain ketones are believed to interact with HLE similarity to the aldehyde and TFMK series of inhibitors. Although studies showing that they are true transition-state analogue inhibitors have not been reported, the formation of the covalent hemiketal adduct was documented in an X-ray crystallographic study of a DFK bound to PPE [150]. One notable finding is that the acidic N-terminal substituents first used by Trainor and co-workers to produce TFMKs with good in vivo profiles... 

In this section, the various correlations will be described with the focus on Level A correlation. Level A is the one offering biggest scope. This correlation that uses all the available data is the only one to allow a full in vivo profile to be simulated from a set of in vitro data. For this reason, this level and only this one is recognized to allow in vitro data to be a surrogate of in vivo for postapproval change. " ... 

In a level B correlation, the mean in vitro dissolution time is compared to either the mean residence time or the mean in vivo dissolution time (Figure 46.2). A level B IVIVC uses the principles of statistical moment analysis. Even though a level B correlation uses all the in vitro and in vivo data, it is not considered a point-to-point correlation. It does not uniquely reflect the actual plasma concentration-time profile because a number of different in vivo profiles will produce similar mean residence times. For this reason, a level B correlation is of little value from a regulatory point of view. 

Satoh A, Nagatomi Y, Hirata Y et al (2009) Discovery and in vitro and in vivo profiles of 4-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-l, 3-thiazol-2-yl]-N-methy lbenzamide as novel class of an orally active metabotropic glutamate receptor 1 (mGluRl) antagonist. Bioorg Med Chem Lett 19 5464-5468... 

Based upon its in vitro and in vivo profile in rodents consistent with antipsychotic activity, its efficacy in a primate model of predictive of antipsychotic activity, and a decreased propensity for causing motor disturbances in haloperidol-sensitized squirrel monkeys, Cl-1007 was chosen for development as an antipsychotic agent. During develop-... 

Despite its good overall in vivo profile, compound 85 showed only 50 nM potency in the [3H] spiperone binding assay. However when binding... 

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